Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes.

Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine).

From mechanistic studies on artemisinin derivatives to new modular antimalarial drugs.

In the first part of this account, the antimalarial drug artemisinin is presented, and the current hypotheses on the mechanism of action of this endoperoxide-based drug are reviewed. The alkylating ability of artemisinin and synthetic analogues toward heme related to their antimalarial efficacy are underlined. Some possible ways for discovery of new drugs, especially the design of trioxaquines, new active molecules recently patented that have been prepared by covalent attachment of a trioxane residue having alkylating ability to a quinoline moiety known to easily penetrate within infected erythrocytes, are presented.

Alkylating capacity and reaction products of antimalarial trioxanes after activation by a heme model.

The reactivity of 1,2,4-trioxane molecules 2-5, structurally related to the antimalarial drug artemisinin, with a heme model, manganese(II) tetraphenylporphyrin, is reported. With the pharmacologically active drugs 2-4, covalent adducts were obtained by addition of a drug-derived radical onto the porphyrin macrocycle, whereas no reaction was obtained with the nonactive compound 5. This confirms that alkylation is probably one of the key factors of the pharmacological activity of endoperoxide-based antimalarial drugs.

Characterization of the Main Radical and Products Resulting from a Reductive Activation of the Antimalarial Arteflene (Ro 42-1611).

The peroxide-containing antimalarial drug arteflene (Ro 42-1611) generates an alkyl radical after the reductive homolytic cleavage of the peroxide bond in the presence of a heme model Mn(II)(TPP). This alkyl radical has been trapped by TEMPO, and the different products of the reduction activation of arteflene have been characterized. These data suggest that, in these experimental conditions, arteflene is not a significant alkylating agent compared to artemisinin, a trioxane-containing antimalarial drug.